The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes.
X-ray crystallography
cytochrome P450 enzymes
enzyme mechanism
heterocycles
metalloenzymes
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
ISSN: 1521-3765
Titre abrégé: Chemistry
Pays: Germany
ID NLM: 9513783
Informations de publication
Date de publication:
06 Sep 2023
06 Sep 2023
Historique:
received:
30
04
2023
medline:
8
9
2023
pubmed:
20
6
2023
entrez:
20
6
2023
Statut:
ppublish
Résumé
The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen- and sulfur-containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4-(thiophen-2-yl)benzoic acid and 4-(thiophen-3-yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels-Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X-ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4-(thiophen-3-yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4-(Furan-2-yl)benzoic acid was oxidized to 4-(4'-hydroxybutanoyl)benzoic acid using a whole-cell system. This reaction proceeded via a γ-keto-α,β-unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds.
Identifiants
pubmed: 37338048
doi: 10.1002/chem.202301371
doi:
Substances chimiques
Cytochrome P-450 Enzyme System
9035-51-2
Benzoic Acid
8SKN0B0MIM
Oxides
0
Thiophenes
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202301371Subventions
Organisme : Australian Research Council
ID : DP140103229
Organisme : Australian Research Council
ID : DP180103047
Informations de copyright
© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
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